https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9314716/
Etsin tietoa intravirionaalisesta sinkin sijoituksesta Ennen kun virion on aloittanut infektiota ihmiseen. miten sinkki sijoitautuu intravirionaalisesti Rdp partikkelin ja nukleokapsidin ja virionin sisäpinnan suheen tässä C-terminaali-trimeerissä, joka on IDP luonteinen. . mutta omaa runsasti cystein aminohappoa, joka voi sitoa sinkkejä. fysiologisissa oloissa. Viimeiset Sars-cov-2 versiot eivät kirjoita ORF 7 tai ORF8:aa proteiineiksi ja näsitä ,mainitaan tässä sitaatissa. sinkkiä sitovina.
https://www.frontiersin.org/articles/10.3389/fmolb.2020.00222/full
SARS-CoV-2 Virion Stabilization by Zn Binding
Zinc plays a crucial role in the process of virion maturation inside the host cell. The accessory Cys-rich proteins expressed in SARS-CoV-2 by genes ORF7a and ORF8 are likely involved in zinc binding and in interactions with cellular antigens activated by extensive disulfide bonds. In this report we provide a proof of concept for the feasibility of a structural study of orf7a and orf8 proteins. A conceivable hypothesis is that lack of cellular zinc, or substitution thereof, might lead to a significant slowing down of viral maturation.
. Introduction
The SARS-CoV-2 open reading frames ORF7a and ORF8 code for virion non-structural, called accessory (Coffin et al., 1997), proteins of yet unknown function (orf7a and orf8, respectively, hereafter). The protein orf7a is common to all SARS-CoV type coronaviruses and highly conserved (Wu A. et al., 2020), while orf8 is remarkably different from proteins coded by genes ORF8 and ORF8b of human SARS-CoV (Xu et al., 2020).
The orf7a protein of SARS-CoV-1 has been shown to interact with several host proteins (Vasilenko et al., 2010). An analogous situation occurs in the case of the very similar SARS-CoV-2 orf7a protein (Gordon et al., 2020). The most supported hypothesis proposed for orf7a protein function is the interference with virion budding tethering (Bonifacino and Glick, 2004) operated by cellular antigens (Taylor et al., 2015). Indeed, orf7a is expressed in the host cell to inhibit the intracellular (at endoplasmic membrane) process of virion immobilization before and after virion vesiculation. On the basis of structural similarities (Swiecki et al., 2013) we argue that also protein orf8 can be involved in the same inhibition process, strengthening the inhibition of virion immobilization. This conjecture is in agreement with Gordon et al. (2020) where it is suggested that orf8 plays a role in vesicle trafficking and in endoplasmic reticulum protein quality control, thus favoring the reconfiguration of ER/Golgi trafficking during coronavirus infection.
Virion tethering is mainly due to proteins of the tetherin family, also known as bone marrow stromal antigen 2 (BST2) or cluster of differentiation 317 (CD317). BST2 is expressed in many cells in the interferon-dependent antiviral response pathway. The mechanism of tethering involves tetherin protein dimerization via formation of extended disulfide bonds within the coiled coil region (Le Tortorec et al., 2011). This step is known to be strongly influenced by divalent cations involved in Cys binding. Among these ions, the most available in cells is Zn2+.
A timely computational search for therapeutic targets of SARS-CoV-2 found the orf7a-BST2 complex as a potential target to be addressed with structural studies (Wu C. et al., 2020).
The orf7a and orf8 protein sequences (both 121 amino acids long) hint at a high Zn binding propensity, as they display 6 Cys/3 His and 7 Cys/4 His side-chains, respectively, with motifs that are able to bind Zn, thus forming multiple zinc finger (ZF) domains.
The relevance of Zn in the viral replication process has been widely investigated (Chaturvedi and Shrivastava, 2005; Chasapis, 2018) and, indeed, two ZF domains have been discovered in the nucleocapsid protein of HIV-1 (Ncp7) (Morellet et al., 1998; Guo et al., 2000). Two such similar Zn domains have been also identified (Kirchdoerfer and Ward, 2019) along the highly conserved, within the SARS-CoV family (Xu et al., 2020), nsp12 polymerase.
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